Background: Gastric cancer, one of the leading causes of cancer-related death, is strongly associated withH. pyloriinfection, although other risk factors have been identified. The sirtuin (Sirt) family is involved in the tumorigenesis of gastric cancer, and sirtuins can have pro- or anti-tumorigenic effects. Methods: After determining the overall survival rate of gastric cancer patients with or without Sirt6 expression, the effect of Sirt6 upregulation was also tested using a xenograft mouse model. The regulation of Sirt6 and Sirt1, leading to the induction of mouse double minute 2 homolog (MDM2) and reactive oxygen species (ROS), was mainly analyzed using Western blotting and immunofluorescence staining, and gastric cancer cell (SNU-638) death associated with these proteins was measured using flow cytometric analysis. Results: Sirt6 overexpression led to Sirt1 suppression in gastric cancer cells, resulting in a higher level of gastric cancer cell death in vitro and a reduced tumor volume. ROS and MDM2 expression levels were upregulated by Sirt6 overexpression and/or Sirt1 suppression according to Western blot analysis. The upregulated ROS ultimately led to gastric cancer cell death as determined via Western blot and flow cytometric analysis. Conclusion: We found that the upregulation of Sirt6 suppressed Sirt1, and Sirt6- and Sirt1-induced gastric cancer cell death was mediated by ROS production. These findings highlight the potential of Sirt6 and Sirt1 as therapeutic targets for treating gastric cancer.
背景：胃癌作为癌症相关死亡的主要原因之一，与幽门螺杆菌感染密切相关，尽管其他风险因素也已得到确认。Sirtuin（Sirt）家族参与胃癌的肿瘤发生，且不同Sirtuin成员可能具有促癌或抑癌作用。方法：在确定表达或不表达Sirt6的胃癌患者总体生存率后，通过异种移植小鼠模型验证Sirt6上调的影响。主要采用蛋白质印迹法和免疫荧光染色分析Sirt6与Sirt1的调控机制及其诱导的小鼠双微体2同源蛋白（MDM2）与活性氧（ROS）表达，并通过流式细胞术检测胃癌细胞（SNU-638）中相关蛋白表达引起的细胞死亡。结果：Sirt6过表达可抑制胃癌细胞中Sirt1的表达，导致体外胃癌细胞死亡率升高及体内肿瘤体积缩小。蛋白质印迹分析显示，Sirt6过表达和/或Sirt1抑制可上调ROS与MDM2表达水平。通过蛋白质印迹与流式细胞术证实，上调的ROS最终引发胃癌细胞死亡。结论：本研究发现Sirt6上调可抑制Sirt1表达，且Sirt6与Sirt1诱导的胃癌细胞死亡由ROS生成介导。这些发现揭示了Sirt6与Sirt1作为胃癌治疗靶点的潜在价值。
Sirt6-Mediated Cell Death Associated with Sirt1 Suppression in Gastric Cancer
肿瘤(癌症)患者之家